Synthesis, Reactivity and Biological Activity of 17β-HSD1 Inhibitors Based on a Thieno[2,3-d]pryrimidin-4(3H)-one Core

Breast cancer is the most common cancer in women in Western countries. In the early stages of development most breast cancers are hormone-dependent, and estrogens, especially estradiol, have a pivotal role in their development and progression. One approach to the treatment of hormone-dependent breast cancers is to block the formation of the active estrogens by inhibiting the action of the steroid metabolising enzymes. 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is a key enzyme in the biosynthesis of estradiol, the most potent female sex hormone. The 17beta-HSD1 enzyme catalyses the final step and converts estrone into the biologically active estradiol. Blocking 17beta-HSD1 activity with a specific enzyme inhibitor could provide a means to reduce circulating and tumour estradiol levels and thus promote tumour regression. In recent years 17beta-HSD1 has been recognised as an important drug target. Some inhibitors of 17beta-HSD1 have been reported, however, there are no inhibitors on the market nor have clinical trials been announced. The majority of known 17beta-HSD1 inhibitors are based on steroidal structures, while relatively little has been reported on non-steroidal inhibitors. As compared with 17beta-HSD1 inhibitors based on steroidal structures, non-steroidal compounds could have advantages of synthetic accessibility, drug-likeness, selectivity and non-estrogenicity. This study describes the synthesis of large group of novel 17beta-HSD1 inhibitors based on a non-steroidal thieno[2,3-d]pyrimidin-4(3H)-one core. An efficient synthesis route was developed for the lead compound and subsequently employed in the synthesis of thieno[2,3-d]pyrimidin-4(3H)-one based molecule library. The biological activities and binding of these inhibitors to 17beta-HSD1 and, finally, the quantitative structure activity relationship (QSAR) model are also reported. In this study, several potent and selective 17beta-HSD1 inhibitors without estrogenic activity were identified. This establishment of a novel class of inhibitors is a progressive achievement in 17beta-HSD1 inhibitor development. Furthermore, the 3D-QSAR model, constructed on the basis of this study, offers a powerful tool for future 17beta-HSD1 inhibitor development. As part of the fundamental science underpinning this research, the chemical reactivity of fused (di)cycloalkeno thieno[2,3-d]pyrimidin-4(3H)-ones with electrophilic reagents, i.e. Vilsmeier reagent and dimethylformamide dimethylacetal, was investigated. These findings resulted in a revision of the reaction mechanism of Vilsmeier haloformylation and further contributed to understanding the chemical reactivity of this compound class. This study revealed that the reactivity is dependent upon a stereoelectronic effect arising from different ring conformations.

Portrait of Mathilde Wiener Monasch (?) d.1864.

Mrs. Monasch is shown as a young woman wearing a gray translucent shawl and a lace bonnet with ornate flaps coming down over the ears. Some of her black hair is showing. She is shown in a 3/4 view; the eyes are lustrous, the corners of the mouth are raised in a half smile. On backing of original frame: "Zum Andencken von Ihren Schwiegersohn, J. Wollstein d. 20th February 1839" (In memory of your son-in-law J. Wollstein Feb 20th, 1839).

Genetic control of flowering in spotted gum, Corymbia citriodora subsp. variegata and C. maculata

Genetically controlled asynchrony in anthesis is an effective barrier to gene flow between planted and native forests. We investigated the degree of genetically controlled variation in the timing of key floral developmental stages in a major plantation species in subtropical Australia, Corymbia citriodora subsp. variegata K.D. Hill and L.A.S Johnson, and its relative C. maculata K.D. Hill and L.A.S. Johnson. Flowering observations were made in a common garden planting at Bonalbo in northern New South Wales in spring on 1855 trees from eight regions over three consecutive years, and monthly on a subset of 208 trees for 12 months. Peak anthesis time was stable over years and observations from translocated trees tended to be congruent with the observations in native stands, suggesting strong genetic control of anthesis time. A cluster of early flowering provenances was identified from the north-east of the Great Dividing Range. The recognition of a distinct flowering race from this region accorded well with earlier evidence of adaptive differentiation of populations from this region and geographically-structured genetic groupings in C. citriodora subsp. variegata. The early flowering northern race was more fecund, probably associated with its disease tolerance and greater vigour. Bud abundance fluctuated extensively at the regional level across 3 years suggesting bud abundance was more environmentally labile than timing of anthesis. Overall the level of flowering in the planted stand (age 12 years) was low (8–12% of assessed trees with open flowers), and was far lower than in nearby native stands. Low levels of flowering and asynchrony in peak anthesis between flowering races of C. citriodora subsp. variegata may partially mitigate a high likelihood of gene flow where the northern race is planted in the south of the species range neighbouring native stands

Pressure and alloying effects on the metal to insulator transition in NiS2-xSex studied by infrared spectroscopy

The metal to insulator transition in the charge-transfer NiS2-xSex compound has been investigated through infrared reflectivity. Measurements performed by applying pressure to pure NiS2 (lattice contraction) and by Se alloying (lattice expansion) reveal that in both cases an anomalous metallic state is obtained. We find that optical results are not compatible with the linear Se-alloying vs pressure-scaling relation previously established through transport, thus pointing out the substantially different microscopic origin of the two transitions.

Uriah P. Levy collection undated, 1787-1948, 1959, 1961, 1985, 2005.

Contains the notebook and correspondence of Abram Kanof relating to the naval career and activities of Uriah P. Levy; the correspondence, memoranda, newspaper clippings, and a manuscript paper of Isaac Markens pertaining to the alleged claim that Levy was instrumental in abolishing flogging in the Navy; personal documents including a letter to Captain E.A.F. Lavalette concerning the behavior of officers under Levy's command as commodore of the Mediterranean fleet (1859), a photostatic copy of his will and the inventory of his estate (1862), and published material by and about Uriah Phillips Levy including a bound typewritten copy of "Record of Naval Court of Inquiry, 1857;" An essay on flogging in the Navy, 1849; Memorial of Uriah P. Levy, ... 1855; an original copy of a Manual of rules for men-of-war by Captain U.P. Levy, 1862; and Monticello and its preservation, since Jefferson's death, 1862-1902, by George Alfred Townsend. Also contains the halitza of Virginia Lopez Levy, widow of Uriah P. Levy, 1866, signed by J.J. Lyons; copies of letters of Michael Levy to Henry Deering and Dudley Woolridge, 1787-1788, and a published copy of The defense of Captain Jonas P. Levy. Gift, in part, of the Elsie O. and Philip D. Sang Foundation, 1979 and of Herman Herst, Jr., 1987.

Vykopirovka s pereselencheskikh uchastkov Komzeta Kolaǐskoǐ dachi razverst. Dzhankoǐskogo raǐona za No. No. 1, 2, 3, 4 5,6 i Maǐfel'd

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Cover for plans regarding theRaitendorf and Maĭfelʻd tracts of land in the Dzhankoĭ region

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Vykopirovka iz plana otvodov d. Kodymo v uchastok KOMZET Dzhankoĭ polerodcheskoĭ dachi razverstanii︠a︡

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1-D hydrogen-bonded organization of hexanuclear {3d-4f-5d} complexes: evidence for slow relaxation of the magnetization for [{LMe2Ni(H2O)Ln(H2O)4.5}2{W(CN)8}2] with Ln = Tb and Dy

Heterometallic {3d-4f-5d} aggregates with formula [{LMe2Ni(H2O)Ln(H2O)4.5}2{W(CN)8}2]·15H2O, (LMe2 stands for N,N-2,2-dimethylpropylenedi(3-methoxysalicylideneiminato) Schiff-base ligand) with Ln = Gd, Tb, Dy, have been obtained by reacting bimetallic [LMe2Ni(H2O)2Ln(NO3)3] and Cs3{W(CN)8} in H2O. The hexanuclear complexes are organized in 1-D arrays by means of hydrogen bonds established between the solvent molecules coordinated to Ln and the CN ligands of an octacyanometallate moiety. The X-ray structure was solved for the Tb derivative. Magnetic behavior indicates ferromagnetic {W–Ni} and {Ni–Ln} interactions (JNiW = 18.5 cm-1, JNiGd = 1.85 cm-1) as well as ferromagnetic intermolecular interactions mediated by the H-bonds. Dynamic magnetic susceptibility studies reveal slow magnetic relaxation processes for the Tb and Dy derivatives, suggesting SMM type behavior for these compounds.

Plan uchastka kolfonda litera "D" Krivorogskogo okruga Mikhăilovskogo raĭona, ploshchadiʻ︠u︡ 874 desi︠a︡tin

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Plan uchastka kolfondalitera "D" Krivorogskogo okruga Mikhaĭlovskogo raĭona ploshchchadiʻ︠u︡ 874 desi︠a︡tin

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Vykopirovka s proektnogo plana Kurmanskoĭ D.R. Dzhankoĭskogo raĭona

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Conformational analysis of D-pantothenic acid

The conformational analysis of d-pantothenic acid using classical semiempirical methods has been carried out. The pantothenic acid molecule can exist in the neutral form (I) or in the ionised form (II) with a deprotonated negatively charged carboxyl group. The neutral molecule as well as the anion is highly flexible and has an ensemble of several allowed conformations rather than one or two unique conformations. The distribution of allowed conformations indicate that the β-alanine as well as the pantoic acid part of the molecule prefers partially folded conformations. The conformation of the former is greatly affected by the ionisation state of the carboxyl group whereas that of the latter is not. Possibility of intramolecular hydrogen bonding in different allowed conformations has also been explored. A bifurcated hydrogen bond involving a carboxyl (or carboxylate) oxygen atom and a hydroxyl oxygen atom, as acceptors, and the amide nitrogen atom as the donor occurs frequently in both I and II. Amongst the two crystal structures containing pantothenic acid reported so far, the conformation of the molecule in l-lysine d-pantothenate lies in the allowed region and is stabilised by a bifurcated intramolecular hydrogen bond, whereas that in the calcium bromide salt falls in a disallowed region, presumably due to the requirement of tridentate metal coordination.